Table 2.

Summary of recommendations for the management of common adverse events associated with dinutuximab beta treatment in patients with high-risk neuroblastoma

Adverse event	Management recommendation
Pain	Non-opioid analgesics Paracetamol or ibuprofen are recommended for the first cycle(s) of dinutuximab beta treatment. In painless consecutive cycles, the omission of non-opioids can be considered Gabapentin Start prior to and continue during dinutuximab beta infusion  Start at 10 mg/kg/day 3 days prior to infusion, increase to 2 × 10 mg/kg/day and 3 × 10 mg/kg/day in 2 consecutive days before the infusion  Gabapentin 3 × 10 mg/kg/day can be interrupted between courses or given continuously. It should be tapered off at discontinuation of dinutuximab beta Morphine: Start prior to and continue during dinutuximab beta infusion. Aim for the lowest dose of morphine required for the shortest possible time  Prior to dinutuximab beta infusion, start continuous i.v. morphine infusion (0.02–0.05 mg/kg/h) or administer bolus (0.05–0.1 mg/kg/h) 2 h before infusion  During dinutuximab beta treatment, continue morphine at 0.03 mg/kg/h or higher if needed  With daily infusions of dinutuximab beta, morphine infusion can be continued at a decreased rate (e.g. 0.01 mg/kg/h) for 4 h after the end of dinutuximab beta infusion For pain uncontrolled by gabapentin, morphine or non-opioid analgesics, additional i.v. ketamine is recommended. Adjusting the rate and dose of dinutuximab beta infusion should also be considered Hyoscine butylbromide may be given to manage abdominal pain
Fever	Prophylactic antipyretics such as paracetamol or metamizole (where licensed) can be given Fever can be treated with paracetamol, ibuprofen or metamizole (where licensed) Blood cultures should be taken to rule out an infection Febrile neutropenia should be treated with antibiotics according to local guidelines at least until blood cultures return a negative result and the patient does not present with other features suggestive of active bacterial infection Fever persisting more than 48−72 h despite adequate management should prompt ruling out other causes of fever (e.g. fungus, virus, etc.) as per local guidelines If fever is not extremely high and is well tolerated, supportive therapy may not be needed
Hypersensitivity reactions	i.v. antihistamines (e.g. diphenhydramine) should be administered ~ 20 min before each dinutuximab beta infusion and repeated every 4–6 h as required  Oral antihistamines may also be given the day before dinutuximab beta infusion For grade 1−2 reactions, dinutuximab beta might be interrupted or the infusion rate reduced and symptoms treated For grade ≥ 3 reactions, dinutuximab beta should be interrupted immediately and symptoms treated For severe, life-threatening reactions, the infusion should be stopped immediately and dinutuximab beta treatment should be permanently discontinued. i.v. antihistamine, adrenaline and steroids should be administered  Intramuscular adrenaline or slow i.v. adrenaline may also be used in patients with anaphylaxis  The use of steroids should be limited to severe and life-threatening reactions For more detailed guidance, see flow charts in Fig. 2
Capillary leak syndrome	Blood pressure and weight should be monitored regularly to guide management Mild symptoms may require fluid management:  Fluids may be given or restricted dependent on weight/blood pressure and local protocols Severe symptoms should be managed with fluid restriction  Diuretics should be used with caution  Furosemide may be given to manage severe weight gain with lung oedema or ascites  In severe cases, human albumin solution might be used if albumin levels are low  Some patients may require oxygen support for hypoxaemia For very rare, severe symptoms, dinutuximab beta infusion may be slowed or interrupted
Visual disturbances	Patients with pupillary palsy may temporarily require corrective glasses Sunglasses are recommended for patients whose symptoms are exacerbated by sunlight 1% pilocarpine can be given to improve symptoms Patients should undergo complete ophthalmological examination and be monitored
Diarrhoea	For mild diarrhoea, fluids should be given For severe diarrhoea, loperamide or racecadotril can be administered
Neurotoxicity	For moderate neuropathy, dinutuximab beta should be interrupted and may be resumed once symptoms have resolved For severe peripheral neuropathy or transverse myelitis, the infusion should be stopped immediately and dinutuximab beta treatment should be permanently discontinued; i.v. IgG and high-dose steroids should be administered
Hepatotoxicity	No management required if no other symptoms present If transaminase levels are < 20 times normal, patients should be monitored closely Concomitant hepatotoxic drugs should be avoided
Haematological toxicities	Generally, no management required other than support with blood products according to local practice
Laboratory abnormalities	Generally, no management required Ion disturbances should be monitored frequently and fluids should be corrected if needed

IgG immunoglobulin, i.v. intravenous